Dataset Information

Comparison of four 11C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios.

ABSTRACT: Translocator protein (TSPO) is a biomarker for detecting neuroinflammation by PET. 11C-(R)-PK11195 has been used to image TSPO since the 1980s. Here, we compared the utility of four 11C-labeled ligands-(R)-PK11195, PBR28, DPA-713, and ER176-to quantify TSPO in healthy humans. For all of these ligands, BP ND (specific-to-non-displaceable ratio of distribution volumes) was measured by partially blocking specific binding with XNBD173 administration. In high-affinity binders, DPA-713 showed the highest BP ND of 7.3 followed by ER176 (4.2), PBR28 (1.2), and PK11195 (0.8). Only ER176 allows the inclusion of low-affinity binders because of little influence of radiometabolites and high BP ND. If inclusion of all three genotypes is important for study logistics, ER176 is the best of these four radioligands for studying neuroinflammation.

SUBMITTER: Fujita M

PROVIDER: S-EPMC5643834 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Comparison of four 11C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios.

Fujita Masahiro M Kobayashi Masato M Ikawa Masamichi M Gunn Roger N RN Rabiner Eugenii A EA Owen David R DR Zoghbi Sami S SS Haskali Mohamad B MB Telu Sanjay S Pike Victor W VW Innis Robert B RB

EJNMMI research 20171016 1

Translocator protein (TSPO) is a biomarker for detecting neuroinflammation by PET. 11C-(R)-PK11195 has been used to image TSPO since the 1980s. Here, we compared the utility of four 11C-labeled ligands-(R)-PK11195, PBR28, DPA-713, and ER176-to quantify TSPO in healthy humans. For all of these ligands, BP ND (specific-to-non-displaceable ratio of distribution volumes) was measured by partially blocking specific binding with XNBD173 administration. In high-affinity ...[more]

PMID: 29038960

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Project description:IntroductionQuantitative positron emission tomography (PET) studies of neurodegenerative diseases typically require the measurement of arterial input functions (AIF), an invasive and risky procedure. This study aims to assess the reproducibility of [11C]DPA-713 PET kinetic analysis using population-based input function (PBIF). The final goal is to possibly eliminate the need for AIF.Materials and methodsEighteen subjects including six healthy volunteers (HV) and twelve Parkinson disease (PD) subjects from two [11C]-DPA-713 PET studies were included. Each subject underwent 90 min of dynamic PET imaging. Five healthy volunteers underwent a test-retest scan within the same day to assess the repeatability of the kinetic parameters. Kinetic modeling was carried out using the Logan total volume of distribution (VT) model. For each data set, kinetic analysis was performed using a patient-specific AIF (PSAIF, ground-truth standard) and then repeated using the PBIF. PBIF was generated using the leave-one-out method for each subject from the remaining 17 subjects and after normalizing the PSAIFs by 3 techniques: (a) Weightsubject×DoseInjected, (b) area under AIF curve (AUC), and (c) Weightsubject×AUC. The variability in the VT measured with PSAIF, in the test-retest study, was determined for selected brain regions (white matter, cerebellum, thalamus, caudate, putamen, pallidum, brainstem, hippocampus, and amygdala) using the Bland-Altman analysis and for each of the 3 normalization techniques. Similarly, for all subjects, the variabilities due to the use of PBIF were assessed.ResultsBland-Altman analysis showed systematic bias between test and retest studies. The corresponding mean bias and 95% limits of agreement (LOA) for the studied brain regions were 30% and ± 70%. Comparing PBIF- and PSAIF-based VT estimate for all subjects and all brain regions, a significant difference between the results generated by the three normalization techniques existed for all brain structures except for the brainstem (P-value = 0.095). The mean % difference and 95% LOA is -10% and ±45% for Weightsubject×DoseInjected; +8% and ±50% for AUC; and +2% and ± 38% for Weightsubject×AUC. In all cases, normalizing by Weightsubject×AUC yielded the smallest % bias and variability (% bias = ±2%; LOA = ±38% for all brain regions). Estimating the reproducibility of PBIF-kinetics to PSAIF based on disease groups (HV/PD) and genotype (MAB/HAB), the average VT values for all regions obtained from PBIF is insignificantly higher than PSAIF (%difference = 4.53%, P-value = 0.73 for HAB; and %difference = 0.73%, P-value = 0.96 for MAB). PBIF also tends to overestimate the difference between PD and HV for HAB (% difference = 32.33% versus 13.28%) and underestimate it in MAB (%difference = 6.84% versus 20.92%).ConclusionsPSAIF kinetic results are reproducible with PBIF, with variability in VT within that obtained for the test-retest studies. Therefore, VT assessed using PBIF-based kinetic modeling is clinically feasible and can be an alternative to PSAIF.

Project description:Neuroinflammation plays a key role in neuronal injury after ischemic stroke. PET imaging of translocator protein 18 kDa (TSPO) permits longitudinal, noninvasive visualization of neuroinflammation in both preclinical and clinical settings. Many TSPO tracers have been developed, however, it is unclear which tracer is the most sensitive and accurate for monitoring the in vivo spatiotemporal dynamics of neuroinflammation across applications. Hence, there is a need for head-to-head comparisons of promising TSPO PET tracers across different disease states. Accordingly, the aim of this study was to directly compare 2 promising second-generation TSPO tracers, 11C-DPA-713 and 18F-GE-180, for the first time at acute and chronic time points after ischemic stroke. Methods: After distal middle cerebral artery occlusion or sham surgery, mice underwent consecutive PET/CT imaging with 11C-DPA-713 and 18F-GE-180 at 2, 6, and 28 d after stroke. T2-weighted MR images were acquired to enable delineation of ipsilateral (infarct) and contralateral brain regions of interest (ROIs). PET/CT images were analyzed by calculating percentage injected dose per gram in MR-guided ROIs. SUV ratios were determined using the contralateral thalamus (SUVTh) as a pseudoreference region. Ex vivo autoradiography and immunohistochemistry were performed to verify in vivo findings. Results: Significantly increased tracer uptake was observed in the ipsilateral compared with contralateral ROI (SUVTh, 50-60 min summed data) at acute and chronic time points using 11C-DPA-713 and 18F-GE-180. Ex vivo autoradiography confirmed in vivo findings demonstrating increased TSPO tracer uptake in infarcted versus contralateral brain tissue. Importantly, a significant correlation was identified between microglial/macrophage activation (cluster of differentiation 68 immunostaining) and 11C-DPA-713- PET signal, which was not evident with 18F-GE-180. No significant correlations were observed between TSPO PET and activated astrocytes (glial fibrillary acidic protein immunostaining). Conclusion: 11C-DPA-713 and 18F-GE-180 PET enable detection of neuroinflammation at acute and chronic time points after cerebral ischemia in mice. 11C-DPA-713 PET reflects the extent of microglial activation in infarcted distal middle cerebral artery occlusion mouse brain tissue more accurately than 18F-GE-180 and appears to be slightly more sensitive. These results highlight the potential of 11C-DPA-713 for tracking microglial activation in vivo after stroke and warrant further investigation in both preclinical and clinical settings.

Dataset Information

Comparison of four 11C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios.

Publications

Comparison of four <sup>11</sup>C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios.

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